INVITED REVIEW

Proton Pump Inhibitor Use in Infants:

FDA Reviewer Experience

Ii-Lun Chen,
Wen-Yi Gao,
Aisha P. Johnson,
Ali Niak,
John Troiani,
Joyce Korvick,


Nancy Snow, zKristina Estes, yAmy Taylor, and
Donna Griebel

ABSTRACT
The Food and Drug Administration has completed its review of 4 clinical
trials evaluating the use of proton pump inhibitors (PPIs) in infants (ages
1 month to <12 months) for the treatment of gastroesophageal reflux disease
(GERD). An Advisory Committee meeting was held in November 2010 to
discuss the potential reasons why PPI use in these trials failed to show a
benefit in infants with GERD, and directions for future study. The present
review summarizes the findings from the clinical trials. Potential mechanisms for the failed clinical trials are discussed. The safety of long-term use is
also discussed. As a result of our analysis and review, the authors agree with
the Advisory Committee members that PPIs should not be administered to
treat the symptoms of GERD in the otherwise healthy infant without the
evidence of acid-induced disease.
Key Words: Advisory Committee, clinical trials, efficacy, GERD, infants,
proton pump inhibitor, safety

(JPGN 2012;54: 814)

he use of proton pump inhibitors (PPIs) in infants has

increased over time. Among pediatric patients <12 months
old, there was an 11-fold increase in the number of new prescriptions dispensed between 2002 and 2009 (1).
Comprehensive guidelines recently published by the North
American Society for Pediatric Gastroenterology, Hepatology, and
Nutrition-European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN-ESPGHAN) state that gastroesophageal reflux disease (GERD) is present when the reflux of gastric
contents causes troublesome symptoms and/or complications (2).
Because of the unique characteristics of the infant stomach, feeding
schedule, and acid production compared with older children and
adults, gastric refluxate enters the esophagus much more frequently

Received May 18, 2011; accepted August 15, 2011.

From the
Division of Gastroenterology and Inborn Errors Products, the
yPediatric and Maternal Health Staff, Office of New Drugs, and the
zDivision of Clinical Pharmacology III, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug
Administration, Silver Spring, MD.
Address correspondence and reprint requests to Wen-Yi Gao, MD, PhD,
Division of Gastroenterology and Inborn Errors Products, Bldg 22,
10903 New Hampshire Ave, Silver Spring, MD 20993-0002 (e-mail:
wen-yi.gao@fda.hhs.gov).
Drs Ii-Lun Chen and Wen-Yi Gao participated equally in the preparation of
this manuscript and share first authorship.
This article reflects the views of the authors and does not necessarily
represent FDA policy.
The authors report no conflicts of interest.
Copyright # 2012 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e31823890b4

than in adults (3). In most infants, this does not cause distress, and is
designated as gastroesophageal reflux (GER); if it causes distress, it is
designatedGERD(2).ThepresentreviewpertainstoPPIuse inGERD.
The natural history of symptomatically (nonendoscopically)
diagnosed GERD in infancy, particularly spitting up, is spontaneous
resolution (4). Once a patient presents with signs of GERD (regurgitation, crying, arching back), management in primary care settings usually begins with a trial of conservative measures such as
thickened, frequent, and smaller feeds, and frequent burping. If the
infant responds favorably, conservative measures are maintained
until resolution; however, if the infant does not respond, other
etiologies, such as anatomic anomalies and cow milk protein
intolerance, are evaluated. In routine clinical practice, if conservative measures and a search for alternative etiologies fail to relieve
signs and symptoms, then antacids, H2 blockers, or PPIs may be
initiated. The NASPGHAN guidelines state in infants with unexplained crying and/or distressed behavior that expert opinion
suggests that if irritability persists with no explanation other than
that of suspected GERD, the risk/benefit ratio of a time-limited
(2-week) trial of antisecretory therapy is not clear (2). The
guideline cautions that there are potential side effects of the PPIs,
and that clinical improvement following empiric therapy may be
because of spontaneous symptom resolution.
There are presently no PPIs approved by the Food and Drug
Administration (FDA) for use in infants younger than 12 months.
Four randomized controlled trials have been completed in infants
with a clinical diagnosis of symptomatic GERD. None of the PPI
studies (esomeprazole, lansoprazole, pantoprazole, or omeprazole)
demonstrated efficacy in infants with GERD. The present review
summarizes the efficacy results of these trials, and available
pharmacokinetic (PK), pharmacodynamic (PD), and safety data
in infants. Given the absence of benefit attributable to PPI use in
otherwise healthy infants without a documented acid-induced condition, their use in GERD cannot be recommended.

PATIENTS AND METHODS

Data Sources
The following publically available data sources for these 4
PPIs (esomeprazole (5), lansoprazole (6), pantoprazole (5), omeprazole (7)) were used in this analysis:
1. FDA Clinical Reviews of New Drug Applications submitted by
drug manufacturers (applications were reviewed involving
AstraZenecas esomeprazole [NEXIUM] and omeprazole
[PRILOSEC]; Takedas lansoprazole [PREVACID]; and
Pfizers pantoprazole [PROTONIX])
2. FDA Advisory Committee (AC) meeting proceedings from
November 5, 2010
3. PPI utilization data presented at a June 2010 FDA Pediatric AC
meeting to review safety of PPIs in the pediatric age group.

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Volume 54, Number 1, January 2012

Clinical Trial Selection

To date, 4 randomized controlled trials have been completed
evaluating use of PPIs to treat clinically diagnosed GERD in infants
ages 1 month to <12 months. These trials were conducted by
pharmaceutical companies in response to requests by the FDA.
Pediatric Written Requests were issued for trials of omeprazole,
lansoprazole, pantoprazole, and esomeprazole under the authority of
the Food and Drug Modernization Act (8). Postmarketing requirements to conduct trials were initially issued for lansoprazole, pantoprazole, and esomeprazole under the Pediatric Rule, and later upheld
under authority given by the Pediatric Research Equity Act (9).

Data Extraction
Data were extracted directly from the publically available
FDA Clinical Reviews.

Study Populations
The study population characteristics in these trials are shown
in Table 1. All of the trials, except that for omeprazole, exclusively
enrolled patients between 1 and 12 months of age (5,6). For
omeprazole, the 1 to <12 months age group made up 90% of
the study population (7). All of the studies enrolled fewer than 100
patients per study arm and permitted enrollment of infants with a
diagnosis of GERD based on clinical presentation. Enrolled infants
were to be otherwise healthy, meaning that infants who had
clinically significant medical conditions (eg, gastrointestinal anatomic disorders, serious infections, unstable organ diseases, use of
certain concomitant medications) were excluded. Endoscopy and
other procedures (eg, pH-metry) were not required, and only a few
patients in these studies had previous endoscopy.

Study Designs
The designs of these trials are summarized in Table 2.

Proton Pump Inhibitor Use in Infants: FDA Reviewer Experience

differences. In the case of the omeprazole trial, which was
single-blinded and lacked a placebo control group, between-group
comparisons to the lowest (0.5 mg/kg) dose group were not statistically significant (5,6). For omeprazole, mean daily vomiting/
regurgitation episodes decreased by 4.34, 2.97, and 4.35 episodes
per day (during the last 72 hours) in the 0.5-, 1.0-, and 1.5-mg/kg
dose groups, respectively, and all of the confidence intervals
included zero (7). Interpretation of the omeprazole data is limited
by the trials single-blinded, uncontrolled design and its inclusion of
some patients (10%) older than 12 months of age (7).

Safety
No deaths occurred in any of the infant PPI trials. The most
common adverse events were upper respiratory infection, fever,
cough, and diarrhea, conditions seen frequently in this age group.
There were no clinically significant findings in laboratory
measures, including hematology and chemistry, or in vital signs
and physical examination.
In the clinical trials of esomeprazole and lansoprazole, there
were no clinically meaningful differences of the common adverse
events between the treated groups and placebo groups. For pantoprazole, otitis media, rhinitis, laryngitis, and elevated creatine
kinase were more common in the treated group compared with
the placebo group (difference of 4%). The clinical significance of
these differences is not clear. The omeprazole trial had a doseranging design. It did not appear that there were more adverse
events with dose escalation. The incidences of the adverse events
were comparable across the 4 PPIs. Of note, the trials were
relatively brief in duration, 4 to 8 weeks, so the ability to make
conclusions regarding the safety profile for longer periods of
exposure in this population is limited.

Additional Information
PK and PD information were used to select the PPI doses for
infants in the randomized controlled trials. These data are
summarized below.

Study Primary Endpoints

Pharmacokinetics

The primary efficacy endpoints used in these trials are listed

in Table 3.

Primary Efficacy

The PK of 3 PPIs, esomeprazole, lansoprazole, and pantoprazole, have been studied in infants ages 1 month to 1 year. A
granule formulation of each drug was developed for use in these
pediatric studies. Two dose levels were included in each PK study
(Table 5). PK parameters for all 3 drugs were greatly variable in this
age group.

The primary efficacy results of the 4 PPI trials are shown in

Table 4. In the clinical trials of esomeprazole, lansoprazole, and
pantoprazole, which were double-blinded and placebo-controlled
trials, there were no statistically significant between-group

Esomeprazole
The PK of oral esomeprazole was evaluated
in 35 infants who received either 0.25 or 1 mg  kg1  day1 for
7 days (10). Mean esomeprazole exposure in infants who received

RESULTS

TABLE 1. Population characteristics of phase III PPI trials in infants

Population characteristic
Age, 1<12 mo
Sample size, per arm
Clinical diagnosis of GERD

Esomeprazole

Lansoprazole

Pantoprazole

Omeprazole

Yes
40
Yesy

Yes
80
Yesy

Yes
50
Yesy

Yes

35
Yesz

Referenced from Data Sources Section. GERD gastroesophageal reflux disease; PPI proton pump inhibitor.


Study population was 024 months age group; 90% of patients were younger than 12 months.
y
Patients had signs of GERD or endoscopically proven GERD.
z
Patients had signs of GERD for at least 2 months.

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TABLE 2. Study designs of PPI efficacy and safety trials in infants

Study design feature

Esomeprazole

Lansoprazole

Pantoprazole

Omeprazole

Randomized
Control group
Blinding
Trial of conservative measures
Open-label enrichment phase to identify PPI responders
Randomized withdrawal from PPI
Antacids allowed
Length of randomized phase

Yes
Placebo
Double
No
Yes (2 wk)
Yes
Yes (as rescue)
4 wk

Yes
Placebo
Double
Yes
No
No
No
4 wk

Yes
Placebo
Double
Yes
Yes (4 wk)
Yes
Yes (as rescue)
4 wk

Yes
Dose ranging
Single
Yes
No
No
Yes
8 wk

Referenced from Data Sources Section. PPI proton pump inhibitor.

1 mg  kg1  day1 was similar to that in children 1 to 11 years who

received 10 mg/day, adolescents who received 20 mg/day, and adults
who received 20 mg/day. Infants who received 0.25 mg  kg1  day1
had exposures that were 76% to 82% lower than exposures observed
in other age groups who received 10 to 20 mg/day.

Lansoprazole
The PK of oral lansoprazole was evaluated in
24 infants who received 1 or 2 mg  kg1  day1 for 5 days (11). Mean
lansoprazole exposure in infants who received 1 mg  kg1  day1
was similar to children 1 to 11 years old who received a weight-based
regimen of either 15 or 30 mg/day for children 30 or >30 kg,
respectively. The exposure in these infants was similar to
adolescents (1217 years) and adults who receive 30 mg/day.
Mean lansoprazole exposure in infants who received 2 mg  kg1 
day1 was approximately 2- to 3-fold higher than exposures observed
in adolescents and adults who receive 30 mg/day.
Pantoprazole
The single-dose PK of oral pantoprazole was
evaluated in 21 infants who received an average dose of 0.6 mg/kg
and in 20 infants who received an average dose of 1.2 mg/kg (12).
Dosing in this trial was not based on weight; instead, a single-dose

level was assigned to a particular weight band, as described in

Table 5. Mean pantoprazole exposure in infants who received the
average dose of 1.2 mg/kg was 20% to 35% lower than adults who
received a single dose of 40 mg but similar to children (611 years)
and adolescents (1217 years) who received 40 mg/day. Mean
pantoprazole exposure in infants who received the average dose
of 0.6 mg/kg was 70% to 78% lower than children (611 years),
adolescents (1217 years), and adults who received a single
40-mg dose.

Pharmacodynamics
Two dose levels were included in each infant PD study
(1012). Intragastric pH and percentage time pH exceeded 4 were
evaluated. The utility of these PD endpoints in the management of
infant symptomatic GERD has not been established. No consistent
dose-response relation was observed for the 3 PPIs for which data
are available. The data from these studies are summarized in
Table 6.
The PD effect, as measured by the percent time pH > 4
during the 24-hour dosing interval, is greater than or equal to the
response observed in adults. This trend suggests that appropriate

TABLE 3. Primary endpoints of phase III PPI trials in infants

Proton pump inhibitor
Esomeprazole (NEXIUM)
Lansoprazole (PREVACID)

Pantoprazole (PROTONIX)
Omeprazole (PRILOSEC)

Primary endpoint
Time from randomization to discontinuation
because of symptom worsening

Responderz rate in randomized double-blind
treatment period
Proportion of patients who withdrew because
of lack of efficacy
Change from baseline in daily mean
vomiting/regurgitation episode frequency
during last 72 h

Assessment tool for primary endpoint

PGAy of patients GERD signs
Daily diary of patients GERD signs
by parent/caregiver, PGA,
and physical examination
Patient diary rating of various signs
associated with GERD
Patient diary card and PGA

Referenced from Data Sources Section. GERD gastroesophageal reflux disease; PGA Physicians Global Assessment.


Symptom class included vomiting/regurgitation, irritability, supraesophageal and respiratory disturbances, and feeding difficulties; Parent and Physician
Symptom Severity Assessment Scale included none (0), mild (1), moderate (2), and severe (3); symptom worsening defined as worsening by 1 ordinal category
based on physician assessment of parental reports.
y
Physicians Global Assessment: Overall clinical impression of the patients GERD-related symptoms during the last 7 days as none (no symptoms), mild
(symptoms present but not interfering with daily activities), moderate (symptoms present and somewhat interfering with daily activities), or severe (symptoms
present and greatly interfering or preventing daily activities).
z
Patient was defined as a responder if he/she had 50% reduction from baseline in number of feeds with crying/fussiness/irritability or in average duration
of such episodes.

Lack of efficacy: significant worsening of GERD symptoms, and/or maximal antacid use for 7 consecutive days, and/or worsening esophagitis on
endoscopy, and/or physician judgment.

10

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TABLE 4. Primary efficacy results of phase III PPI trials in infants

PPI medication

Primary efficacy result relative to control

Esomeprazole

Hazard ratio 0.69 (PPI/placebo)

95% CI 0.351.35
(P 0.275)
Responder rate (PPI vs placebo)
54.3% (44/81) vs 54.3% (44/81)
(P 1.000)
Responder rate (PPI vs placebo)
12% (6/52) vs 11% (6/54)
(P 1.000)
Adjusted LS means (ANCOVA)
:
0.5 mg/kg dose 4.34 (8.5 to 0.15)
1.0 mg/kg dose 2.97 (7.0 to 1.06)
1.5 mg/kg dose 4.35 (8.2 to 0.46)
(All pairwise comparisons to 0.5 mg/kg
dose had P > 0.50)

Lansoprazole

Pantoprazole

Omeprazole

Referenced from Data Sources Section. ANCOVA analysis of covariance; CI confidence interval; LS least square; PPI proton pump inhibitor.


Adjusted least square means (ANCOVA): 3 patients from intent-to-treat
population were excluded as extreme outliers.

doses were selected for study in the infant trials. Although there is a
clear dose-response relation for esomeprazole from 0.25 to
1 mg  kg1  day1, the dose-response relation for lansoprazole
and pantoprazole is less apparent. For lansoprazole, this may be
because of a selection of doses that were at or above the maximum
effective dose. In addition, PD data were available from only
3 patients in each lansoprazole dose group.

FDAs Gastrointestinal Drugs Advisory

Committee Meeting, November 5, 2010
On November 5, 2010, a Gastrointestinal Drugs AC meeting
was held to discuss the results from the 4 randomized controlled
trials of PPIs in pediatric patients with symptomatic GERD, who
were younger than 12 months. AC members were screened for
potential conflicts of interest in accordance with applicable laws,
regulations, and policies. To interpret the consistently negative
results from these trials, the committee re-evaluated the pathophysiology, diagnosis, and management of GERD, and issues related to
the trials designs. A brief summary of the proceedings follows.

Proton Pump Inhibitor Use in Infants: FDA Reviewer Experience

In adults, symptomatic GERD is known to be secondary to
acid reflux, as is erosive esophagitis in infants. In contrast, for most
infants with classic signs and symptoms of GERD, acid reflux has
never been demonstrated to be causative, but transient relaxation of
the lower esophageal sphincter probably plays a role. The AC
suggested that for future pediatric studies of acid-suppressing
agents for symptomatic GERD, pediatric trials in infants should
be limited to acid-induced conditions (eg, erosive esophagitis). For
example, certain pediatric populations have underlying conditions
that predispose them to acid-induced pathology (eg, neurological
diseases, congenital esophageal lesions, tracheal esophageal fistula).
The AC generally agreed that for new products intended to
treat pediatric conditions in which acidity is a key contributor,
pediatric clinical trials are needed to obtain PD and PK and longterm safety data. In these cases, efficacy can be extrapolated from
adult data. The effect of CYP450 enzyme ontogeny on PPI PKs
should be investigated in relation to dosing in the various pediatric
age groups (age groups may be categorized as neonates [0<1
month], infants [1 month<1 year], children [111 years], and
adolescents [1217 years]).
Most AC members concurred that use of endoscopy and
instruments, measuring patient-reported outcomes (eg, the Infant
Gastroesophageal Reflux Questionnaire) in clinical trials of infants
with symptomatic GERD, should be explored further. Data on
posttreatment repeat endoscopies and more guidance on performing
biopsies in this patient population are needed. Traditional pH-probe
monitoring, although useful in measuring the PD effect of PPIs, is
not useful as a primary clinical outcome measure because pH and
GERD symptoms are poorly correlated. Multichannel intraluminal
impedance monitoring may be considered for use in future studies
because it provides improved time-event relation and detection of
both acid and nonacid reflux compared with traditional pH probes.
Improved detection of reflux associated with retrograde bolus
movement and differentiation between acid and nonacid reflux
may allow us to select appropriate patient populations when evaluating PPIs for GERD. In addition, biomarkers of tissue injury
should be explored.

DISCUSSION
Despite a lack of evidence to support their effectiveness in
infant symptomatic GERD, PPI use in infants has increased over
time. Among pediatric patients younger than 12 months, nearly
404,000 prescriptions were dispensed to 145,000 patients nationwide in 2009 (1,13). This represents an 11-fold increase in prescriptions from 2002. Interestingly, the proportion of new patient
prescriptions for any PPI decreased in this age group during the
years 2002 to 2009. This indicates that although new prescription
use was decreasing, chronic use was likely increasing, resulting in

TABLE 5. Mean PK parameters following oral administration of PPIs in infants

PPI medication

Dose

Esomeprazole

0.25 mg/kg
1 mg/kg
1 mg/kg
2 mg/kg
2.5 mg (2.5<7 kg); 5 mg (715 kg)
5 mg (2.5<7 kg); 10 mg (715 kg)

Lansoprazole
Pantoprazole

Cmax, ng/mL

135
494
959
2087
503
1384

(123) n 17
(150) n 17
(49) n 12
(75) n 12
(100) n 21
(94) n 20

AUC, ng  h/mLy
463
1834
2203
5794
1137
3709

(113) n 9
(103) n 7
(104) n 12
(97) n 12
(99) n 13
(90) n 18

Percent coefficient of variation, data from references in corresponding text. PK pharmacokinetic; PPI proton pump inhibitor.


Cmax, peak plasma concentration.
y
AUC, area under the plasma concentration time curve.

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TABLE 6. Mean PD parameters of 3 PPIs in infants

Intragastric pH

PPI medication

Dose, mg/kg

Baseline

Steady state

Esomeprazole

0.25
1
1
2
0.6
1.2

2.3 (n 25)
2.2 (n 23)
NA
NA
4.2 (n 11)
3.1 (n 10)

3.6 (n 22)
5.6 (n 22)
NA
NA
4.8 (n 11)
4.2 (n 10)

Lansoprazole
Pantoprazole

Percent time intragastric pH > 4

Baseline
30.5
28.6
50
52.4
55.5
32.2

(n 25)
(n 23)
(n 3)
(n 3)
(n 11)
(n 10)

Steady state
47.9
69.3
84.9
83.9
68.5
56.6

(n 22)
(n 22)
(n 3)
(n 3)
(n 11)
(n 10)

Referenced from corresponding text. NA not available; PD pharmacodynamic; PPI proton pump inhibitor.


Median values for esomeprazole, mean values for pantoprazole.

an overall increase in PPI prescriptions. General practice/family

medicine and internal medicine were the top prescribing specialties
of PPIs for all of the pediatric age groups in 2009. Esophageal
Disorder Not Elsewhere Classified (ICD-9 530.8) was the top
diagnosis code recorded for all of the age groups for the review
period (14). Among the US commercially insured population, the
median age of initiation of PPIs in pediatric patients younger than
2 years was 226 days. The median duration of use for children
12 years of age and younger was 60 days (15). In a retrospective
observational study using data from 1999 to 2004 from 4 health care
plans in the United States involving 2469 infants younger than
12 months, Barron et al (16) report a mean age of first PPI use of 4 to
5 months, with treatment discontinued in most patients by 7 to
8 months of age.
Several key issues should be considered when using PPIs in
infants: whether an individual infants GERD presentation is acid
related, gastrin effects, strength of evidence that PPIs are effective
for treatment of GERD in this population, and long-term safety.

Gastric Acid Secretion and PPI Use in Infants

The use of PPIs to treat GERD in infants is based on the
assumption that acid reflux is the cause of their GERD symptoms.
What is known about the relative contribution of gastric acid to
GERD in the adult versus pediatric population is an important issue to
consider. Although a study by Boyle et al (17) found that
acid secretion rates adjusted by body weight (milliequivalent per
kilogram per hour) in adults were similar to acid secretion rates for
infants younger than 1 year, other studies that did not adjust for body
weight (milliequivalent per hour) found that acid secretion rates of
adults are significantly higher than infants, with the rate varying from
study to study (1821). For example, the maximal acid secretion rate
on the first day of life is approximately 0.03 mEq/hour, which is about
430-fold lower than adults (13.06 mEq/hour) (1823). By the end of 4
months, the average secretion rate of infants is about 27-fold lower
than adults (0.47 vs 13.06 mEq/hour) (19). It is unclear whether body
weightadjusted esophageal acid exposure provides the most
relevant means of comparing infants to adults. Other important
factors affecting acid exposure of the esophageal epithelium in infants
include lower esophageal sphincter tone and feeding frequency,
neither of which requires body weight adjustment. Reflux of nonacidic stomach contents may cause GERD symptoms in infants such
as fussiness, arching, regurgitation, or burping (24).

Gastrin and Rebound Hypersecretion

It has been reported that adult patients experience acid
rebound after withdrawal of PPI therapy, which can lead to PPI

12

dependency (25). Reports in the pediatric literature have also shown

that gastrin levels are elevated in the majority of pediatric patients
(infants through adolescents) on prolonged PPI therapy, but elevated gastrin levels return to normal in 23% to 38% of patients after
long-term treatment (26).
Among the 4 infant PPI trials, only the pantoprazole trial
collected serum gastrin measurements. After 4 weeks of open-label
treatment with pantoprazole, mean gastrin levels increased approximately 50% over baseline. At the final assessment after a 4-week
randomized treatment period, the mean gastrin level in patients
randomized to pantoprazole remained elevated, whereas in those
randomized to placebo gastrin levels trended back toward baseline.
There was no evidence of symptom rebound during the withdrawal
phase, despite elevated gastrin levels at the end of the open-label
phase; however, the observed outcomes may have differed if
concomitant antacid therapy had been controlled.

Absence of Evidence That PPIs Are Effective for

Treatment of GERD in Infants
Although the PK and PD data indicated that appropriate
PPI doses had been identified to suppress gastric acid, all of the
clinical trials conducted to investigate whether 4 different PPIs
were effective for treatment of GERD in infants failed to demonstrate PPI efficacy in this population. The consistency in this
observed outcome suggests that the symptoms upon which the
clinical diagnosis of GERD was made for infants who entered these
trials (eg, fussiness, regurgitation, gagging with feeds) are not
manifestations of acid reflux disease. Alternatively, the endpoints
used in the trials may not have been adequate; however, the
endpoints were based on assessments of classic symptoms that
are the foundation for making the clinical diagnosis of GERD in
infants. For this reason, the endpoints do seem clinically relevant
because they are the symptoms that cause parents to seek care for
their infant.

Long-term and Serious Safety Concerns With

PPI Use
There are potential risks associated with PPI use (2). Clinical
trials of PPIs in infants are of short duration (48 weeks). The
adverse events observed associated with short-term use cannot be
assumed to be the same as those when PPIs are used during long
periods of time. Although PPIs generally have been considered safe,
there are safety concerns associated with long-term use.
Among adults, there have been concerns that long-term PPI
use may predispose patients to an increased risk of gastric cancer,
gastric carcinoid tumors, and colorectal cancer. These concerns are
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based on hypergastrinemia, alteration of the distribution of gastritis,

and accelerated development of atrophic gastritis, in the presence
of Helicobacter pylori infection (27). Suppression of gastric acid
secretion may also predispose patients to certain infections
(Clostridium difficile infections, other enteric infections, and respiratory infections, including community-acquired pneumonias). The
mechanism for this may be that acid suppression eliminates a
defense against pathogens (28).
There have been rare reports of vitamin and electrolyte
abnormalities (eg, vitamin B12 (29) deficiency and hypomagnesemia (30)) in adults taking PPIs chronically. There have been cases
of hypomagnesemia that required discontinuation of the PPI in
addition to magnesium supplementation (31). Observational studies
and postmarket reports (32) of calcium deficiency and osteoporosis
in adults on chronic PPI therapy recently led FDA to require class
labeling of these adverse effects for all PPIs; however, further
studies are needed to discern the exact mechanism for these
fractures. It is not known whether calcium malabsorption fully
accounts for this observation. Additionally, PPIs have been implicated as a cause of acute interstitial nephritis (29).
Within the context of the small trials of relatively short
duration described in this review, PPIs appeared relatively safe in
infants younger than 1 year. In the literature, there have been reports
of adverse events related to the use of chronic PPIs in infants; for
example, acid suppression has been linked to higher rates of
necrotizing enterocolitis in extremely low-birth weight infants
(33). We do not yet fully understand the consequences of reduced
gastric acid on the intestinal microflora of infants. The safety
concerns associated with PPI use in adults, including negative
effects on bone integrity, are important to consider for children.
An appropriate assessment of the risk/benefit of PPI use in infants
requires an understanding of their therapeutic benefit in this population.

SUMMARY
The FDA reviewed 4 randomized controlled trials evaluating
the use of PPIs in infants (ages 1 month to <12 months) for the
treatment of symptomatic GERD. An AC meeting was held in
November 2010 to discuss the pathophysiology and diagnosis of
infant GERD and possible reasons why the trials failed to show
effectiveness, despite the use of a range of endpoints to assess
efficacy. Based on FDAs independent review and the expert advice
of the AC members, the authors offer the following conclusions:
1. Clinical efficacy was not demonstrated in the controlled clinical
trials evaluated, even though the pharmacodynamic studies
predicted that the PPI doses evaluated in these trials would have
raised the gastric pH. In the absence of demonstrated efficacy of
PPIs for the treatment of GERD in infants, the authors agree
with the AC members that health care practitioners should not
prescribe PPIs for the otherwise healthy infant, 1 month to
<12 months old, as initial treatment for symptomatic GERD.
Rather, infants with symptoms of GERD should be initially
treated with conservative measures (eg, infant positioning and
changes in diet) and evaluated for milk protein allergy. The
majority of these infants improve over time with conservative
measures and do not have acid induced disease that will benefit
from PPI administration. If conservative measures and a search
for alternative etiologies fail to relieve signs and symptoms,
then consultation with a pediatric gastroenterologist may be
warranted for further evaluation and management.
2. Use of PPIs should be reserved for infants with an
endoscopically documented acid-induced condition such as
erosive esophagitis. The risk/benefit relation of administration
of PPIs in infants with GER or GERD without a documented
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Proton Pump Inhibitor Use in Infants: FDA Reviewer Experience

acid-induced condition is not favorable because no benefit can
be attributed to the PPI. Furthermore, there may be risks
associated with long-term PPI use that require further study in
this young population.
3. Data from short-term PPI trials in infants have not revealed a
serious safety signal; however, both short-term and long-term
safety data are limited.
4. Presently available diagnostic tools such as symptom scores,
survey instruments, and pH-metry are not sufficient to identify
the subpopulation of infants with GER that have acid-induced
disease that could benefit from PPI use. Multichannel
impedance monitoring may be considered in trials of acidsuppressing agents. Endoscopy may be the most reliable
method to identify acid-induced esophageal injury.
5. Clinical trials evaluating PPIs may be warranted in subpopulations of infants such as those with erosive esophagitis, cystic
fibrosis, and short bowel syndrome (34). In infants with erosive
esophagitis, PPI efficacy can be extrapolated from adults;
however, trials are needed to determine the appropriate infant
dose and evaluate safety. PPIs are frequently used in patients
with extraesophageal manifestations of GERD, repairs of
anomalies involving the upper and lower gastrointestinal tract,
and prematurity (34). These populations also should be
considered for enrollment in clinical trials to evaluate PPIs.

Acknowledgments: The authors thank Julie Beitz, MD; Andrew

Mulberg, MD; Sue-Chih Lee, PhD; Patty Greene, PharmD; and
David Moeny, RPh, MPH for providing comments on the article.

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